Cardiovascular disease is a leading cause of morbidity and mortality. It has been shown that the early stages of cardiovascular disease can be diagnosed by assessing the ability of the arteries to dilate in response to an increase in blood flow. The degree of arterial dilation in response to an increased blood flow correlates with the severity of cardiovascular disease.
Endothelial cells constitute the innermost lining of blood vessels and produce nitric oxide, which is the predominant vasodilator in the arterial system. An increase in blood flow results in increased shear stress at the surface of endothelial cells and initiates a signaling pathway that results in phosphorylation and activation of nitric oxide synthase, and increased production of nitric oxide. In addition to acting as a potent vasodilator, endothelium-derived nitric oxide inhibits many of the initiating steps in the pathogenesis of atherosclerotic cardiovascular disease, including low-density lipoprotein uptake, white cell adhesion to the vessel wall, vascular smooth muscle proliferation, and platelet adhesion and aggregation.
Brachial artery flow-mediated dilation serves as a measure of the bioavailability of endothelium-derived nitric oxide in patients, and it has been used extensively in large clinical studies to non-invasively detect endothelial dysfunction of the conduit artery.
Several invasive and non-invasive techniques have been developed to evaluate endothelial function. Invasive techniques, which involve intra-coronary or intra-brachial infusions of vasoactive agents, are considered to be the most accurate for the detection of endothelial dysfunction. Due to their highly invasive nature, the use of such techniques is limited and has led to the development of several non-invasive techniques. The ultrasound imaging of the brachial artery is the most commonly employed non-invasive technique for the assessment of the vasomotor response. See, for example, Mary C. Corretti et al. J. Am. Call. Cardiol. 2002; 39:257-265, which is incorporated herein by reference in its entirety. It utilizes continuous electrocardiogram (EKG) gated two-dimensional ultrasound imaging on the brachial artery before and after induction of arterial dilation by five-minute cuff occlusion of the arm. The ultrasound imaging technique is mostly used to assess (1) the changes in the diameter of the brachial artery induced by administration of vasoactive drugs; and (2) flow-mediated dilation, which follows an occlusion of the brachial artery via inflating a cuff around the limb. Once the cuff is released, the blood flow causes shear stress on the endothelium, which, in turn, produces vasoactive substances that induce arterial dilation. The increase in the diameter of the brachial artery in healthy people is higher than that in patients with endothelial dysfunction. However, even in healthy people, the magnitude of the arterial dilation is not sufficient to be reliably determined by the ultrasound imaging technique. A trained and experienced operator is essential in obtaining meaningful data with the ultrasound imaging technique. This difficulty limits the testing of arterial dilation with the ultrasound imaging technique to specialized vascular laboratories.
Most of the existing techniques do not quantify the amount of stimulus delivered to the endothelium nor do they account for other sources of nitric oxide such as the nitric oxide transported and released by the blood cells in response to hypoxemia induced by the temporary occlusion of the brachial artery. It has been shown that these factors can significantly affect the amount of flow-mediated dilation and, therefore, inject additional variability into the test results obtained with equipment that does not account for such factors.
U.S. Pat. No. 6,152,881 (to Rains et. al.), which is incorporated herein by reference in its entirety, describes a method of assessing endothelial dysfunction by determining changes in arterial volume based on measured blood pressure using a pressure cuff. The pressure cuff is held near diastolic pressure for about ten minutes after an artery occlusion until the artery returns to its normal state. The measured pressure during this time is used to determine the endothelial function of the patient. The extended period of applying cuff pressure to the limb affects circulation, which in turn impacts the measurements.
U.S. Pat. No. 7,390,303 (to Dafni), which is incorporated herein by reference in its entirety, describes a method of assessing arterial dilation and endothelial function, in which the relative changes in the cross sectional area of a limb artery are assessed using a bio-impedance technique to monitor cross-sectional area of a conduit artery. Measurements of bio-impedance are difficult to perform. Since bio-impedance measurements involve applying electricity to the skin of the patient, such measurements are poorly tolerated by patients due to skin irritation. Further, the measured signals vary greatly.
U.S. Pat. No. 7,074,193 (to Satoh et al.) and U.S. Pat. No. 7,291,113 (to Satoh et al.) which are incorporated herein by reference in their entirety, describe a method and apparatus for extracting components from a measured pulse wave of blood pressure using a fourth order derivative and an n-th order derivative, respectively.
A clinical need exists for a system and method that are inexpensive, easy to perform, non-invasive, well tolerated by patients, and provide an indication of the ability of arteries to respond to an increase in blood flow.